In 2017, Romania was placed amongst the countries with the highest prevalence of diabetes mellitus (DM). More than 9% of the 18–99 years old population was estimated to suffer from DM [1]. Pregnant women suffering from DM or gestational DM (GDM) are at increased risk of premature birth, with an incidence of 10% and complications that can affect them or the fetus/neonate [1]. The majority of guidelines recommend screening for all pregnant women between 24th and 28th week of gestation with 75-g 2-hour oral glucose tolerance test and all recommend that all women with GDM should undergo a glycemic test at around 6 to 12 weeks after delivery, that breastfeeding is important; in case of future pregnancies, preconception screening should be undergone [2]. Pregnancy-induced hypertension (PIH), preeclampsia, eclampsia, and other metabolic disorders are frequently found in mothers with DM and are associated with an unfavorable progression of pregnancy and poor neonatal outcomes [3]. Newborns of mothers with DM are at great risk of being large for gestational age (LGA), developing neonatal hypoglycemia and hypocalcemia and acute respiratory distress syndrome (ARDS) [4]. Antenatal glucocorticoids represent the standard of care for pregnant women at risk of premature birth at gestational ages between 24 and 34/36 weeks of gestation [5, 6]. There isn’t a uniform consensus about the timing, because the National Institute for Health and Care Excellence and the World Health Organization (WHO) recommendations are for 24 + 0 until 34 + 0 weeks, the American College of Obstetricians and Gynecologists (ACOG) recommendation are for 24 + 0 until 36 + 6 weeks, while the Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations are for 24 + 0 until 34 + 6 weeks of gestation, even though, the gestational age should be known and the pregnant women should be in spontaneous preterm labor, respectively repeatedly regular uterine contractions associated with significant cervical changes. The way of administration has a uniform recommendation, respectively intramuscular dexamethasone or betamethasone [7]. This therapy is associated with a significant decrease in neonatal mortality, the incidence of ARDS, and intraventricular hemorrhage in the neonatal period [8].

Endogenous corticosteroids exert maturational effects on different organs via cellular glucocorticoid and mineralocorticoid receptors. Synthetic corticosteroids like dexamethasone and betamethasone interact only with glucocorticoid receptors [9]. Both of them pass the placenta in their active form and they are resistant to the action of $\beta$-hydroxysteroid dehydrogenase type 2, an enzyme that degrades glucocorticoid hormones coming from the mother [10]. Glucocorticoid receptors are ubiquitous, found in the nucleus of the cell, and play an important role in moderating the genic expression. The complexity of the signaling mechanism via glucocorticoid receptors in the developing fetus has not been yet studied in depth [11]. The best described biochemical effect is on type 1 and 2 pneumocytes and surface epithelial cells of the alveoli. Glucocorticoids stimulate cellular development and surfactant production, therefore preparing the fetus for extrauterine life [12]. Besides the effect on surfactant synthesis, glucocorticoids increase pulmonary compliance and pulmonary total capacity and reduce the passage of proteins from alveolar capillaries to the alveoli, thus contributing to the elimination of pulmonary secretions after birth [13].

Concerning the substance to administer, a multicentric study conducted in 2019 found no difference between dexamethasone and betamethasone in terms of safety and efficiency on decreasing the neonatal complications, and also the morbidity and mortality in the neonatal period [14].

It is important to mention that the subgroup of women with DM was excluded from most clinical studies concerning antenatal glucocorticoid therapy because of the concerns regarding glycemic management [15]. Clinical guidelines recommend treating these women in the same manner as the non-DM women even though there is no recent data to prove the benefit of the therapy in these patients. It is unknown whether these recommendations are applied in clinical practice [16]. This study is a retrospective analysis whose purpose is to evaluate the real-life administration of antenatal glucocorticoids in pregnant women with DM and to analyze the maternal and neonatal prognostic factors, comparing this population with women without DM who gave birth prematurely.

This study comprises data from 67 pregnant women, 33 with DM and 34 non-DM matches by maternal age, parity, body mass index, residence, and ethnicity, who received corticosteroid before prematurely birth in the second largest maternity of Bucharest (approximatively 3500 births/year), in 4 years, respectively between December 2016 and March 2021 and their 70 newborns. Advanced maternal age, rural origin, and primiparity are associated with poor neonatal outcome [17, 18, 19] and could have acted as confounding variables, affecting the study’s results, therefore, the match was carefully selected. Group 1 (control) was formed by 34 non-DM pregnant women, respectively 50.75% of the total and their 36 newborns; group 2, comprised of 33 mothers with DM, respectively 49.75% of the total, who gave birth to 34 newborns. The women in the second group suffered from gestational diabetes mellitus (GDM) diagnosed by 75-g 2-hour oral glucose tolerance testing 78.78% cases, diet-controlled type 2 DM in 15.15% of cases, and 1 case of insulin-treated type 1 DM, respectively 3.03% of cases. 5 twin pregnancies were present in both groups, 2 in group 1 and 3 in group 2. 2 twin pregnancies of the second group were complicated by intrauterine death of one fetus. Therefore, the 33 women from the second group gave birth to 34 viable newborns and the 34 women from the first group gave birth to 36 viable newborns.

Maternal variables taken into account were: admission blood glucose levels, the presence of obesity or excessive weight gain during pregnancy–considered regarding the body mass index before pregnancy as WHO recommended, the presence of complications (PIH, preeclampsia), and the administration of glucocorticoids. For the newborns, we considered: gestational age at birth, absolute birth weight and birth weight relative to gestational age (normal weight, LGA, small for gestational age (SGA)), Apgar score at 1 and 5 minutes, neonatal complications (ARDS, intracranial hemorrhage, hypoglycemia, hypocalcemia) and neonatal deaths.

The cumulative and comparative analysis of all the neonatal and obstetrical parameters of the cases in the two groups and the statistical analysis regarding the significant difference or the frequency of the complications have been analyzed by the chi-square test. The results were interpreted according to the obtained p-value; p 0.05 was considered to be statistically significant.

The analyzed data were collected from the observation charts of the Obstetrics and Gynecology Departments of the Emergency University Hospital of Bucharest and the Statistics Department of the hospital, with the permission of the Ethics Committee (73317/02.12.2021).

According to the American Association of Diabetes, the incidence of PIH and preeclampsia increases proportionally to the increase in glycated hemoglobin [20, 21]. Compared to a low incidence of preeclampsia in non-DM women (2–7%), this complication is diagnosed in 15–20% of pregnancies associated with type one DM and in 10–14% of pregnancies associated with type 2 DM [22]. DM and preeclampsia share multiple risk factors as maternal age, parity, multiple gestations, ethnicity, and obesity. GDM is frequently cited as a risk factor for preeclampsia, although many studies had limitations, not taking into account the common risk factors. A retrospective study conducted in Germany evaluated the association between GDM and preeclampsia, controlling for the common risk factors. The study included 647392 pregnancies. The authors’ conclusion was that the risk for preeclampsia is higher in pregnancies with DM and that DM represents an independent risk factor for the development of preeclampsia [23, 24]. Another retrospective study conducted in the USA, Washington, had similar results. The pregnant women were divided into 5 groups: PIH, moderate preeclampsia, severe preeclampsia, eclampsia, and one control group with none of these complications. After adjusting for confounding variables (body mass index, age, ethnicity, parity), GDM was associated with a 1.5-fold higher risk of moderate and severe preeclampsia and a 1.4-fold higher risk of PIH when compared to the control group [22].

Obesity is a key risk factor for GDM and at the same time represents an independent risk factor for pregnancy complications. Weight above the superior limit of normality is frequently associated with dyslipidemia and hypertension, anomalies that increase the risk of complications during pregnancy [25, 26]. Moreover, maternal obesity plays an important role in the birth of an LGA neonate. In an observational prospective study, the association between obesity and GDM was analyzed. Obesity was more frequent amongst pregnant women with GDM, compared to non-DM patients (70% versus 42.6%, p 0.001) [27].

Corticosteroids administered to the mother prior to the premature birth decrease the morbidity and mortality of the premature newborns [6, 28]. However, the data regarding pregnant women with DM is limited. Clinical guidelines recommend treating them in the same manner as the non-DM women, even if there is no recent data to support the benefit in this subpopulation [16]. Following data analysis, there were no significant differences between the two groups with respect to corticosteroids administration, a considerable number of patients receiving the therapy. The presence of DM does not seem to affect the physicians’ decision on prescribing glucocorticoids for fetal lung maturation. These results are similar to those of a recent study conducted in New Zealand, which found that there is no difference in the manner of administration between the two populations of pregnant women; 25% of the patients received the treatment at a gestational age above 35 weeks, even though the national guideline of New Zealand recommends glucocorticoids up to this gestational age [16]. ACOG recommends the therapy for women at risk of premature birth between 34 0/7 and 36 6/7 weeks only if they had not received a prior course of glucocorticoids [28]. The Society for Maternal-Fetal Medicine supports the use of glucocorticoids in this group of patients, as 70% of preterm births occur in this period [13]. The Antenatal Late Preterm Steroids Trial, conducted by National Institute of Child Health and Human Development, a randomized double-blind study, involved pregnant women with singleton pregnancies at risk of premature birth between 34 0/7 and 36 6/7 gestational weeks. After administration of glucocorticoids for fetal lung maturation, it showed a drop in the need for surfactant administration and respiratory support in newborns during the first 72 hours after birth [29]. The Obstetrics and Gynecology Society from Romania recommends in its guideline from 2019 to use glucocorticoid therapy up to 34 weeks of gestation [6]. In our study, glucocorticoids were administered between 34–36 weeks of gestation in many cases of both groups (12 cases in group 1 and 16 cases in group 2), consistent with ACOG guidelines.

Numerous studies suggest that the risk for premature birth is higher for pregnant women with DM than for those non-DM [3, 5, 30, 31], Sibai et al. [3] sustaining higher rates of premature births prior to 35 weeks of gestation in women with DM. However, in other studies that compared the average length of pregnancy in women with DM versus non-DM women, the average length was significantly higher in mothers with DM (p 0.001) [32]. In our study the majority of patients (19 from group 1 and 24 from group 2) gave birth between 35 and 37 weeks; 18 deliveries from group 1 and 12 from group 2 took place under 35 weeks.

Kevin P Yeagle [33] conducted a retrospective study in 2019 to compare the Apgar score at 1 and 5 minutes between a group of pregnant women with DM and a group of non-DM pregnant women. He found no differences between the two groups. Our results are similar, with no significant differences between the two groups regarding the Apgar score (p $>$ 0.05).

Fetal macrosomia is the most common complication of DM, and is associated with poor management of maternal DM and adverse neonatal outcomes. The concept of excessive fetal growth is expressed by means of two terms: macrosomia and LGA. Also, the fetal growth curve is monitored after the 12th week of gestation, when the biometric measurement begins. The LGA corresponds to a weight above the 90th percentile for gestational age, thus it allows the identification of premature newborns with excessive weight gain [34]. Studies report a high rate of macrosomia or LGA in subjects with DM [35]. 15–45% of newborns of mothers with DM are LGA [36]. A prospective study has compared the neonatal outcomes of 2 groups of pregnant women with DM. One group received an intensive plan of glycemic management while the other received the standard treatment. It seems that even after a strict glycemic control, there were no significant differences with regard to the percent of LGA between the 2 groups [37]. We also found that newborns of mothers with DM are prone to being LGA.

During pregnancy, besides DM, obesity represents an independent risk factor for giving birth to an LGA baby [27]. In the present study, only 5 LGA newborns from group 2 had mothers with normal weight, while the other 10 have been born from obese or overweight women. Therefore, poorly controlled DM may not be the only factor that contributes to excessive fetal growth; it seems that maternal obesity plays an important role too.

DM is a well-known risk factor for neonatal hypoglycemia [4]. In our study, both neonatal hypoglycemia and hypocalcemia were encountered significantly more frequent in the DM group. However, the study that compared neonatal outcomes of mothers following an intensive plan of glycemic management versus the standard therapy found no significant differences between the groups (p = 0.195), with high incidences of neonatal hypoglycemia in both of them (8.7% in the intensive treatment group; 14% in the standard treatment group) [37].

Prematurity represents an important risk factor for ARDS, due to incomplete fetal lung maturation. In 1976 Robert et al. [38] showed that DM is an independent risk factor for ARDS. Newborns of mothers with DM are 5.6 times more likely to develop ARDS than those of non-DM mothers [38]. A meta-analysis conducted in 2019 supports these findings. The analysis included 24 studies and concluded that maternal DM, pre-gestational or GDM, is associated with both prematurity and neonatal ARDS [39]. Intracranial hemorrhage was also associated with both prematurity and DM and antenatal glucocorticoids therapy reduces the risk for these complications in premature newborns [40]. Our results find a similar incidence of ARDS in both groups. Regarding intracranial hemorrhage, there were more cases in group 1, but out of the 6 newborns, 2 were born at 27 gestational weeks and 3 at 28 gestational weeks. Taking into account the fact that births that take place under 28 weeks of gestation are at the highest risk for this complication and 5 out of 6 newborns in group 1 were in this situation, the results are hard to compare.

Premature neonates are at a higher risk of death during the neonatal period and the first year of life compared to those born at term and the rate of mortality increases proportionally with the decrease of gestational age and birth weight [41]. Maternal DM is also associated with a higher mortality rate during the neonatal period than the general population [35]. The 4 neonatal deaths of our study affected premature newborns of 27, 29, 34, and respectively 36 gestational weeks.

The study limitations are the small number of included patients reported to the period of inclusion and the lack of risk of bias assessment.

The administration of antenatal glucocorticoids was not hampered by the presence of maternal DM. In both groups, a considerable number of women received glucocorticoids between 34–36 weeks of gestation, consistent with ACOG recommendations. There were no significant differences regarding Apgar score at 1 and 5 minutes, and the incidence of ARDS was comparable and low in both groups. These findings could suggest that glucocorticoid therapy has the same efficacy in patients with DM. The frequency of LGA newborns and neonatal hypoglycemia was higher in the DM group, but these results might have been influenced not only by poor glycemic control but also by the excess weight and other metabolic anomalies encountered mainly in patients with DM. Considering the low number of patients enrolled in this study and the lack of more specific data regarding the glycemic control of participants with DM, future studies are needed in order to unequivocally prove the benefit of the antenatal glucocorticoid therapy for fetal lung maturation in pregnant women with DM. It is important to emphasize that this study’s findings reflect the local practice and cannot be generalized.

REB designed the research study. AGD and CG collected the data. FF and TS performed the data analysis. AGD and REB performed origibal draft preparation. TS, REB and CG performed the review editing. CB and SDP performed the investigation and validation. FF and SDP performed visualization and funding. All authors read and approved the final manuscript.

All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Emergency University Hospital of Bucharest (number 73317/02.12.2021).

Thanks to all the peer reviewers for their opinions and suggestions.

This research received no external funding.

The authors declare no conflict of interest. REB is serving as one of the Guest editors of this journal. We declare that REB had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to MHD.